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Physiology II
Cardiovascular Physiology
Control Of Peripheral Circulation
Class Notes For 9/30/1999

Alpha one receptors binding with Norepinephrine "…and the alpha one receptors are linked to second messenger systems inside the cell that cause contraction, or cause calcium release, and this is usually that diacylglycerol-IP3 generated system, and phospholipase C, protein kinase C… that whole second messenger system. It catalyzes the formation of these two things (DAP & IP3). The DAP is responsible for opening up receptor operated channels, letting the calcium in. The IP3 is responsible for mobilizing the calcium from the SR and mitochondria, so both these together increase intracellular calcium. One of the things that’s activated by the Calcium-calmodulin complex is phospholipase C and protein kinase C, so all sorts of things can happen inside the cell. So this is the system that cause smooth muscle contraction. And as we go down through the constrictors, almost all of them all by activating this second messenger system, mobilizing calcium. There’s a variety of different kinds of compounds & receptors, but inside the cell, the mechanism is the same. If you’ve got contraction, you’ve got to mobilize the calcium, and once you mobilize the calcium, you get the calcium-calmodulin complex, and then things start to happen. So whether it’s angiotensin, or vasopressin, or serotonin, or muscurinic 3 receptor, they’re all mobilizing calcium and it’s usually by this second messenger system…..

Guyton p. 930 describes more fully:

Phosphatidylinositol System

Some hormones activate transmembrane receptors that then activate the enzyme phospholipase C, which in turn causes some phospholipids in the cell membrane itself to split into second messengers. Types of hormones that do this are mainly local hormones, most notably hormonal factors released by tissue immune and allergic reactions.

The Most Important membrane phospholipid broken down this way is phosphatidyl inositol bisphosphate, and the most important products that serve as second messengers are:

Inositol triphosphate (IP3) and Diacylglycerol (DAP)

Both increase calcium level inside the cell

IP3 mobilizes calcium ions from intracellular sites (mitochondria & SR)

DAP, per Professor Norton, opens receptor-operated calcium channels to bring in extracellular calcium

Per book: DAP activates protein kinase C, which promotes cell division & proliferation

Additionally, lipid portion of DAP contains the precursor to prostaglandins.

Contraction ends when the calcium is removed. The events of relaxation…here you have energy dependent calcium pump (calcium-ATPase), pump in calcium out of the cell, calcium taken back up into the SR and mitochondria, the active MLCK going to inactive because the calcium-calmodulin complex is diminished…when calcium is removed from the cell and MLCK can no longer allow myosin binding to actin then contraction will relax. There’s also some phosphatases involved…but the point is: get rid of the calcium and you get rid of the contraction.

..the Sodium-Calcium exchanger is another way to get calcium out of the cell…sodium into the cell down it’s concentration gradient allowing calcium out of the cell.

Beta Receptor are linked to the second messenger system that drives adenylyl cyclase so what you get with Beta stimulation is increasing cAMP, increased calcium-ATPase activity, increased reuptake of calcium SR and mitochondria. Beta receptors are the prototype way to cause smooth muscle relaxation, which is to turn on cAMP, and activate those processes that remove calcium from the intracellular fluid, and when you do that contraction ends. We have lots of things that act the same way, we have adenosine, histamine, couple other things that cause vasodilation by acting on this adenylyl cyclase system. ALL Beta receptors increase adenylyl cyclase activity. That’s almost the definition of a beta-receptor, a receptor that’s linked with the adenylyl cyclase and turns on its activity. When you think of adrenergic receptors, should really only think of three types:

Then you have:

Relaxation: most of the time, the compounds we talk about cause relaxation by increasing adenylyl cyclase activity, promoting calcium excrusion (from the cytoplasm).

Sue offers contraction question, "If you increase cAMP you’re bringing calcium in so you’re causing contraction." Norton responds, "Only in the heart."

Only in the heart are the beta one receptors linked with calcium channels that allow calcium to come in. So when you activate beta one receptors in the myocardium, you let more calcium come in quicker, but you also activate all these things which remove the calcium quicker and that’s the basis for the shortening systole….the stronger, faster, shorter contraction. But the smooth muscle cells don’t have the link between the beta receptor activation and calcium entry. All they have is a link between beta receptor activation and calcium excrusion. So beta two receptors, on smooth muscle cells, cause relaxation because the calcium goes out quicker. And there’s nothing that corresponds to calcium coming in quicker, it just goes out. That’s the big difference between the beta ones in the heart, and fat cells, and beta twos like on bronchial smooth muscle, blood vessels, and so on. They all increase adenylyl cyclase activity, but then it’s what the cAMP does inside the cell that actually has the effect. Cardiac muscle has this effect: increased calcium ATPase, increased calcium re-uptake into the SR, but it also, just before that, lets more calcium in, so you have a stronger contraction. It doesn’t happen in smooth muscle. It is a good distinction between cardiac muscle, and smooth muscle.

How I (Norton) think about it: Cardiac muscle is a smooth muscle cell that has acquired sarcomeres. It’s organized its actin and myosin into sarcomeres. And the sarcomeric structure acts like skeletal muscle, but the rest of it, but the rest of it acts like smooth muscle. It’s able to spontaneously activate itself, the cells are linked electrically so it functions as a syncytium, it responds to beta receptor activation, lots of smooth muscle characteristics to it plus it’s located in a viscera, not a voluntary muscle location. Allows heart to contract quickly (like skeletal), but contraction lasts a long time (smooth muscle aspect; slow calcium channel effect).

Local Control – Constrictors

Substances that produce smooth muscle constriction by mobilizing calcium, promoting formation of calcium-calmodulin complexes, and these factors are generated locally.

No known substances that are produced as a result of tissue metabolism that vasoconstrict that are locally produced.

Endothelium produces one of the most potent: endothelin.

Endothelin is a small peptide produced by endothelia cells which cause constriction by increasing the activity of the DAP-IP3 system. Produced in response to increased pressure inside the vessel. So when vascular pressure increases, and the endothelium is stretched, the endothelial cells will manufacture & release endothelin. It is not stored in vesicles.

One of the basic properties of smooth muscle cells, is if you stretch it, it will pull back, called myogenic response. It’s true of isolated smooth vessels; so if you could picture a vessel with no endothelium, and you stretched it, it would constrict all by itself. This now is an added mechanism, to produce constriction of a vessel generating a signal to the endothelium. So when arterial pressure/volume is elevated, endothelin is released and it’s a vasoconstrictor. Constriction in response to increased pressure is reasonable response because:

If arterial pressure up, flow up, exceeds needs, tissue limits flow.

Autoregulatory Response keeps blood flow constant in the face of changes in perfusion pressure.

If transient increase, relaxation follows. If chronic, endothelin can lead to restructuring of vessel.

Remodeling is a physical restructuring of the vessel, which will include increased vascular smooth muscle, increased collagen, increased elastin, all the matrix and the wall will hypertrophy. When it hypertrophies, the radius will decrease. Moved from functional vasoconstriction to a structural change in the vessel where the radius is reduced in response to chronically elevated pressures.

If spent a couple days eating salt/vinegar chips, expanding extracellular volume, blood arterial pressure would go up, you get endothelin-mediated vasoconstriction to maintain flows where they’re suppose to be. But if you do it for months & years, the endothelin would mediate a remodeling of the vascular so that the decrease in radius wouldn’t represent constriction, activation of smooth muscle, but just represent a structural change.

Concept of functional (for acute stimuli) to structural change (in response to chronic changes in pressures).

(Responsiveness to endothelin returns when chronic changes completed.)

Example of vein graft remodeling to artery. If anastamosis poor, with turbulent flow, forward velocity decreases, so pressure goes up (Bernouilli), so endothelin released & produces local vascular remodeling at the site. If the disruption is great enough, re-stenosis. Can be responsible for hypertrophic response, and re-stenosis.

Vein graft subjected to the new higher arterial pressure produces endothelin which is responsible for the arterization of the vessel.

Thromboxane (and serotonin) produced by platelets when activated by injury at the site (local). Locally produced & acting; causes constriction and thrombosis formation. Prevents leaking, especially important in cardiovascular homeostasis. Platelets activate enzyme: cyclooxygenase, which allows release of thromboxane & serotonin.. Aspirin inhibits cyclooxygenase – means no thromboxan/serotonin, no coagulation & no vasoconstriction.

Locally acting Dilators

Primary link between level of metabolic activity and control of tissue blood flow

Flow matches Metabolism

Substances produced by metabolism:

CO2, H+, pO2 are three of the primary regulators (also K+, see below)

Also what’s being consumed:

Energy source is ATP, broken down to ADP, down to AMP, then (less last phosphate), Adenosine

Acts as a locally produced hormone, has it’s own set of receptors, on smooth muscles cells, the A2 receptors are linked with adenylyl cyclase system, increasing cAMP activity causing vasodilation. (Not to be confused with alpha-receptors). Adenosine, metabolic breakdown product, probably most important local vasodilator, especially at heart.

In muscle tissue that is repeatedly contracting, increasing interstitial K+ concentrations will also cause vasodilation.

In area of inflammation, Histamine with produced vasodilation via H2 receptors on smooth muscle cells, again increasing cAMP activity.

Adenosine acts on endothelium at A1 receptors and promotes release of Nitric Oxide(NO).

Histamine is also a vasodilator via endothelium at H1 receptors to release NO. These effects on endothelium happen first (NO mediated is first); then as histamine effects smooth muscle cells, have slower, more prolonged vasodilation mediated by the H2 receptor. It’s a di-phasic response, direct & indirect.

Adenosine also binds to receptors on the heart, and A1 receptors on the heart decrease myocardial contractility. That’s important when demands>supply; adenosine concentrations build & produce vasodilation, which will increase oxygen supply. And the adenosine will also act directly on the myocardial cell to decrease contractility therefore decrease oxygen demand. Covers the whole oxygen supply/demand of the heart.

Nitric Oxide is released from the endothelium. Causes vasodilation in smooth muscle cells, via cGMP (not cAMP). Activates protein kinases & produces vasodilation. (Endothelial-derived Relaxing Factor) It is a gas & can diffuse rapidly from its site of production. NO, another stimuli for release is increase in Shear Forces on endothelium. Velocity of flow up, Get a shear-deformation of endothelia cells, stimulates NO.

Which leads to vasodilation. Velocity, therefore goes down. Negative feedback which adjusts vessel diameter to flow velocity.

NO allows a retrograde signal passed backwards, up the cardiovascular system, allowing dilation of larger vessels outside the local system, in response to increase in flow velocity.

Long-term increases in velocity (i.e. exercise training) NO remodels vessel to increase the radius.

Venous graft: connected to arterial system, pressure in it is high, wall arterializes, endothelin promoting vascular hypertrophy, matrix formation, the wall gets thicker, the reason why it doesn’t shut off is that that vessel now has a higher flow in it than it did before. And so you’ve got NO release. NO counteracts the actions of the endothelin so the patency of the graph is maintained by a combination of increased pressure and increased flow velocity. The graft will be successful if those two are balanced off in a way that keeps flow smooth. You get a balance between arterialization/wall thickening and maintain of the diameter.

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